Propofol (2,6-diisopropylphenol), (1), is a low molecular weight phenol that is widely used as an intravenous sedative-hypnotic agent in the induction and maintenance of anesthesia and/or sedation in mammals. The advantages of propofol as an anesthetic include rapid onset of anesthesia, rapid clearance, and minimal side effects (Langley et al., Drugs 1988, 35, 334–372). Propofol may mediate hypnotic effects through interaction with the GABAA receptor complex, a hetero-oligomeric ligand-gated chloride ion channel (Peduto et al., Anesthesiology 1991, 75, 1000–1009.).

Propofol is rapidly metabolized in mammals with the drug being eliminated predominantly as glucuronidated and sulfated conjugates of propofol and 4-hydroxypropofol (Langley et al., Drugs 1988, 35, 334–372). Propofol clearance exceeds liver blood flow, which indicates that extrahepatic tissues contribute to the overall metabolism of the drug. Human intestinal mucosa glucuronidates propofol in vitro and oral dosing studies in rats indicate that approximately 90% of the administered drug undergoes first pass metabolism, with extraction by the intestinal mucosa accounting for the bulk of this presystemic elimination (Raoof et al., Pharm. Res. 1996, 13, 891–895). Because of its extensive first-pass metabolism, propofol is administered by injection or intravenous infusion and oral administration has not been considered therapeutically effective.
Propofol has a broad range of biological and medical applications, which are evident at sub-anesthetic doses and include treatment and/or prevention of intractable migraine headache pain (Krusz et al., Headache 2000, 40, 224–230; Krusz, International Publication No. WO 00/54588). Propofol, when used to maintain anesthesia, causes a lower incidence of post-operative nausea and vomiting (“PONV”) when compared to common inhalation anesthetic agents and numerous controlled clinical studies support the anti-emetic activity of propofol (Tramer et al., Br. J. Anaesth. 1997, 78, 247–255; Brooker et al., Anaesth. Intensive Care 1998, 26, 625–629; Gan et al., Anesthesiology 1997, 87, 779–784). Propofol has also been shown to have anti-emetic activity when used in conjunction with chemotherapeutic compounds (Phelps et al., Ann. Pharmacother. 1996, 30, 290–292; Borgeat et al., Oncology 1993, 50, 456–459; Borgeat et al., Can. J. Anaesth. 1994, 41, 1117–1119; Tomioka et al., Anesth. Analg. 1999, 89, 798–799). Nausea, retching and/or vomiting induced by a variety of chemotherapeutic agents (e.g., cisplatin, cyclophosphamide, 5-fluorouracil, methotrexate, anthracycline drugs, etc.) has been controlled by low-dose propofol infusion in patients refractory to prophylaxis with conventional anti-emetic drugs (e.g., serotonin antagonists and corticosteroids).
Propofol has also been used to treat patients with refractory status epilepticus (Brown et al., Pharmacother. 1998, 32, 1053–1059; Kuisma et al., Epilepsia 1995, 36, 1241–1243; Walder et al., Neurology 2002, 58, 1327–1332; Sutherland et al., Anaesth. Intensive Care 1994, 22, 733–737). Further, the anticonvulsant effects of propofol have also been demonstrated in rat efficacy models at sub-anesthetic doses (Holtkamp et al., Ann. Neurol. 2001, 49, 260–263; Hasan et al., Pharmacol. Toxicol. 1994, 74, 50–53).
Propofol has also been used as an antioxidant (Murphy et al., Br. J. Anaesth. 1992, 68, 613–618; Sagara et al., J. Neurochem. 1999, 73, 2524–2530; Young et al., Eur. J. Anaesthesiol. 1997, 14, 320–326; Wang et al. Eur. J. Pharmacol. 2002, 452, 303–308). Propofol, at doses typically used for surgical anesthesia, has observable antioxidant effects in humans (De la Cruz et al., Anesth. Analg. 1999, 89, 1050–1055). Pathogenesis or subsequent damage pathways in various neurodegenerative diseases involve reactive oxygen species and accordingly may be treated or prevented with antioxidants (Simonian et al., Pharmacol. Toxicol. 1996, 36, 83–106). Examples of specific neurodegenerative diseases which may be treated or prevented with anti-oxidants include, but are not limited to, Friedrich's disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (“ALS”), multiple sclerosis (“MS”), Pick disease, inflammatory diseases and diseases caused by inflammatory mediators such as tumor necrosis factor (TNF) and IL-1.
A significant problem with the formulation and use of propofol is poor water solubility. Accordingly, propofol must be specially formulated in aqueous media using solubilizers or emulsifiers (Briggs et al., Anaesthesia 1982, 37, 1099–1101). For Example, in a current commercial product (Diprivan®, Astra-Zeneca) an oil-in-water emulsion (the emulsifier is the lecithin mixture Intralipid®), is used to formulate propofol (Picard et al., Anesth. Analg. 2000, 90, 963–969). Unfortunately, the oil-in-water emulsion formulation causes discomfort and pain at the site of injection.
One potential solution to the poor water solubility of propofol which avoids the use of additives, solubilizers or emulsifiers and the attendant injection site pain, is a water-soluble, stable propofol prodrug that is converted to propofol in vivo. (Hendler et al., International Publication No. WO 99/58555; Morimoto et al., International Publication No. WO 00/48572; Hendler et al., U.S. Pat. No. 6,254,853; Stella et al., United States Patent Application No. US2001/0025035; Hendler, U.S. Pat. No. 6,362,234; Hendler, International Publication No. WO 02/13810; Sagara et al., J. Neurochem. 1999, 73, 2524–2530; Banaszczyk et al., Anesth. Analg. 2002, 95, 1285–1292; Trapani et al., Int. J. Pharm. 1998, 175, 195–204; Trapani et al., J. Med. Chem. 1998, 41, 1846–1854; Anderson et al., J. Med. Chem. 2001, 44, 3582–3591; Pop et al., Med. Chem. Res. 1992, 2, 16–21). A significant problem with these existing propofol prodrugs is their high stability in vivo. This stability prevents release of therapeutically significant concentrations of propofol, particularly when the prodrug is orally administered.
Accordingly, there is a need for propofol prodrugs, which are sufficiently labile under physiological conditions to provide therapeutically effective concentrations of propofol, particularly, when the prodrug is orally administered.